Drug addiction is a brain disease that is characterized by the compulsive seeking and taking of a drug despite known adverse consequences. A prominent feature of drug addiction is that drug-associated cues can elicit drug-seeking behaviors and contribute significantly to the high propensity to relapse. The development of effective treatment strategies of this disease depends on a thorough understanding of molecular mechanisms underlying the development and extinction of drug-induced behaviors. We have been investigating the notion that the dopamine D1 receptor and the immediate early gene product c-Fos expressed in D1 receptor-bearing neurons mediate the development of persistent neuroadaptation in the brain dopamine system by regulating cell signaling and gene expression. We generated and analyzed novel genetically engineered mouse models and found that the D1 receptor and c-Fos expressed in D1 receptor-bearing neurons mediate the locomotor sensitization and reinforcing effects of cocaine. Moreover, these molecules regulate cocaine-induced dendritic remodeling, electrophysiological responses, and changes in cell signaling and gene expression in the brain. Of particular relevance, a lack of c-Fos expression in D1 receptor-bearing neurons in mice results in no change in the induction but a delayed extinction of cocaine-induced conditioned place preference. Further, synaptic depression is induced in the nucleus accumbens following the acquisition, and this depression is apparently reversed after extinction of the behavior. Extinction training also modifies c-Fos-regulated expression of certain glutamate receptor subunits in the nucleus accumbens. These findings led us to hypothesize that up- regulation of c-Fos expression in D1 receptor-bearing neurons facilitates the extinction of cue-elicited cocaine seeking, and that D1 receptor-mediated and c-Fos-regulated changes in neuronal excitability, cell signaling and gene expression play key roles in the extinction process. The overall goal of this proposal is to test the above hypothesis. In Aim 1, we propose to genetically up-regulate c-Fos expression in D1 receptor-bearing neurons by using a novel D1 receptor neuron-specific inducible c-Fos mouse model, and investigate whether up-regulation of c-Fos facilitates the extinction of cocaine-induced conditioned place preference. In Aims 2 and 3, we propose to identify D1 receptor-mediated and c-Fos-regulated changes in neuronal excitability, signaling and gene regulation that are associated with the acquisition and extinction processes using the two complementary c-Fos mouse models. Based on their key involvement in the circuitry underlying cue-elicited cocaine seeking, we will focus on the nucleus accumbens and basolateral amygdala. Successful completion of the proposed work will establish a molecular framework for the role of c-Fos in the extinction of cue-elicited drug seeking by regulating specific changes in dopamine D1 receptor-expressing neurons in the brain. We expect these experiments to provide novel insights into mechanisms underlying facilitation of extinction of drug seeking, identifying potential new targets for the treatment of drug abuse. PUBLIC HEALTH RELEVANCE: The proposed work will identify how specific changes in neuronal circuits, cellular signaling and gene expression may facilitate the extinction of drug seeking behaviors. These experiments may provide potential new targets for pharmacological and molecular interventions for the treatment of drug abuse.